Cyclic N-substituted derivatives of 1,4-benzene disulphonamide

ABSTRACT

Compounds of the formulae:

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 386,853 filed Aug. 9, 1973.

This invention relates to cyclic N-substituted derivatives of 1,4-benzene disulphonamide which have cerebral vasodilator activity and are therefore useful for treating conditions attributable to a restriction of blood flow to the brain. Such conditions include atherosclerosis, occlusion of blood vessels in the brain, stroke and other cerebrovascular diseases. Particularly useful compounds according to this aspect of the invention are those which have a selective effect on the cerebral vasculature, with a comparatively small effect on blood vessels in other tissues such as peripheral tissue and the kidneys, and so do not cause a serious fall in blood pressure or increase in diuresis.

The aforesaid derivatives include compounds of the formula ##SPC2##

Those of the formula ##SPC3##

And the salts thereof with pharmaceutically acceptable cations wherein n and m are each two or three; X is oxygen or sulphur; R² and R³, when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms; R² and R³, when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R⁴ and R⁵, when taken separately, are each hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms and R⁴ and R⁵, when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R⁴ and R⁵ , when taken separately, and in R⁴ and R⁵, when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms.

Certain of the aforesaid compounds are old in the art as shown in U.S. Pat. No. 3,165,550. Those of the aforesaid compounds of the present invention which are unobvious include compounds of formula (I) and formula (II) and the salts thereof with pharmaceutically acceptable cations wherein n and M are each 2 or 3; X is oxygen or sulphur; R² and R³ , when taken separately, are each alkyl having 1 to 4 carbon atoms; R² and R³ , when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R⁴, when taken separately, is hydroxy or alkoxy having 1 to 5 carbon atoms; R⁵ , when taken separately, is hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms and R⁴ and R⁵, when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R⁴ and R⁵, when taken separately, and in R⁴ and R⁵ , when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms.

Preferred compounds of the invention having cerebral vasodilator activity are those of formula (I) in which X is an oxygen atom. Another preferred group are those compounds of Formula (II) in which Y is a methylene group and R⁴ and R⁵ together represent an oxo group or an alkylene dioxy group having 1 to 4 carbon atoms, each of these being attached to the methylene group, i.e. to Y. Another preferred group of compounds are those of formula (II) wherein Y is methylene, R⁵ is hydroxy or alkoxy having 1 to 5 carbon atoms and R⁴ is hydrogen. Of those preferred compounds of formula (I) in which X is an oxygen atom, particularly preferred are those in which R² and R³ are each alkyl having 1 to 4 carbon atoms. Of those preferred compounds in which Y is a methylene group, particularly preferred are those in which n and m are each 2, i.e., the heterocyclic ring is a 4-methoxypiperidene ring; a 4-hydroxypiperidene ring; a 4-piperidone ring or a dialkyl or alkylene ketal thereof.

The compounds of this invention, other than those in which R⁴ and R⁵ together are an oxo group, may be prepared from 4-sulphamoyl-benzene sulphonyl chlorides of the formula: ##SPC4##

by reaction with a cyclic amine of the formula: ##SPC5##

or with a cyclic amine of the formula: ##SPC6##

in a suitable solvent, e.g., acetone or dichloromethane. Preferably, the reaction is carried out in the presence of an excess of the amine reactant or in the presence of an equivalent amount of an organiz tertiary amine to remove the hydrochloric acid formed in the reaction. The reaction is completed in from 1 to 24 hours at 20°C. or may be carried out at elevated temperatures, i.e., 30 to 100°C. for periods of from 1 to 8 hours. The product may be isolated by simply adding the reaction mixture to normal aqueous hydrochloric acid solution, filtering, washing and recrystallizing from a suitable solvent.

The compounds of this invention may also be prepared from 4-nitrobenzene sulphonyl chloride by reaction first with the cyclic amine of formula (IV) or (V) to form a compound of the formula: ##SPC7##

or of the formula: ##SPC8##

wherein R⁴ and R⁵, together, are not an oxo group, and the compound of formula (VI) or (VII) is then reduced to the corresponding amino compound and the latter converted to the corresponding sulphamoyl compound by diazotization, treatment with sulphur dioxide in the presence of a cupric salt and then with ammonia.

Finally compounds in which R⁴ and R⁵ together are an oxo group are prepared from the corresponding dialkyl or alkylene ketals, i.e., compounds of formula (II) in which R⁴ and R⁵ are two alkoxy groups or an alkylene dioxy group attached to a single carbon atom, by methods well known in the art, e.g., by treatment with concentrated hydrochloric acid in aqueous dimethylformamide.

The salts of the present invention include those based on any pharmaceutically acceptable cation. The preferred pharmaceutically acceptable cations are those of the alkali metals, particularly sodium and potassium. Said salts are easily obtained in accordance with conventional methods. For example, the selected compound of formula (I) or formula (II) is dissolved in an aqueous or alcoholic solution of an alkali metal hydroxide such as sodium or potassium hydroxide and the resulting solution is simply concentrated.

In accordance with the treatment method of the present invention, the herein described compounds can be administered to an affected subject via the oral or parenteral route. Generally, there is a significant effect in increasing cerebral blood flow in cats, dogs and baboons at dose levels of from 2.5 to 25 mg/kg intravenously or from 10 to 50 mg/kg orally when administered three times a day, the effect being cumulative. Although the physician will determine the precise dosage for a human patient, it generally will range from 0.5 to 100 mg/kg for intravenous administration and from 2 to 200 mg/kg for oral administration, each dosage form being administered four times a day.

The compounds of the invention may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For administration orally in the form of tablets or capsules, it has been found advantageous to dissolve or disperse the compound in finely divided form (e.g. 30 microns or less in dimensions) in a matrix of a high molecular weight solid polyethylene glycol, e.g. a polyethylene glycol of average molecular weight 6,000 to 7,500 such as "Carbowax" 6,000. A non-ionic wetting agent as dispersion aid, e.g. a polyoxyethylene mono-stearate of average molecular weight about 1,000 such as "Myrj" 52, is preferably also included. For this type of formulation, the compound together with the dispersion aid may be dissolved in the molten polyethylene glycol and cooled, or alternatively may be mixed as an aqueous dispersion with the polyethylene glycol to form a paste and dried, and then, together with other excipients if desired, either granulated prior to compression into tablets or filled directly into capsules, by techniques well known in the art.

Alternatively, tablets may be formed in which a major part of the excipient is composed of a material which, when compressed, has a slower rate of dissolution than that normally achieved by standard tableting practice. Such materials include sugars and edible aminoacids such as glycine. The compound (in finely divided form) is preferably first mixed with the said material and then granulated with a comparatively small amount of the high molecular weight polyethylene glycol and a dispersion aid, before forming into tablets in the usual way.

For parenteral administration, the compounds, being acidic, are best used in the form of sterile aqueous solutions of their alkali metal (e.g. sodium) salts and such solutions may contain other solutes (e.g. sodium chloride) to ensure the stability of the solutions and their compatibility with body fluids, e.g. blood, when the compound is to be administered intravenously, intramuscularly or subcutaneously. The alkali metal salt solution may conveniently be formed by dissolving the compound (and any other solute required) in the sterile water and adjusting the pH to a value in the range from 10.5 to 12.0 with the appropriate alkali metal hydroxide.

The following examples illustrate preparation of the cerebral vasodilators of this invention.

EXAMPLE I 4-(4-Methoxypiperidinosulfonyl) benzene sulfonamide

To a solution of 25.6 g. (0.1 mole) of 4-sulphamoylbenzene sulphonyl chloride in 250 ml. of acetone at room temperature was added portionwise 38 g. (0.3 mole) of 4-methoxypiperidine. The temperature rose to 50°C. After stirring for one hour the solution was poured into 500 ml. of 1N hydrochloric acid. The product crystallized and the mixture was stirred for 30 min., filtered and washed well with water. After air drying, a recrystallization from acetone (150 ml.)-hexane (250 ml.) yielded 22 g. (69% yield) of product, m.p. 187.5°-189.5°C.

The aforesaid chloride starting material was prepared by adding to a slurry of 172 g. (1 mole) of sulfanilamide in 300 ml. of water at room temperature with stirring, 180 ml. (2.1 mole) of concentrated aqueous hydrochloric acid. The resulting slurry was chilled to 0°C in an acetone-dry ice bath, and then a solution of 72 g. (1.004 moles) of sodium nitrite, dissolved in 125 ml. water, was added from a dropping funnel at such a rate that the temperature never went above 5°C. The addition required about one half hour during which time the solid material dissolved to form (A). Liquid SO₂, from an inverted SO₂ cylinder, was added to 850 ml. of glacial acetic acid, which was cooled in ice, until the weight increased by about 250 g. The solution was placed in a 4 l. beaker, 68 g. (0.4 mole) of cupric chloride dihydrate in water was added, and the mixture cooled to 5°C. The diazonium salt solution (A) was then added with stirring, without ice cooling, as rapidly as foaming would allow. Stirring was continued for 10 min. after the addition was complete. The temperature of the reaction mixture rose to 30°C. Two liters of water and ice were added and the mixture stirred. The product crystallized and stirring was continued for another 15 minutes. The product was filtered and washed well with cold water. After air drying, a recrystallization from 350 ml. of ethyl acetate and 700 ml. of hexane yielded 69 g. (27% yield) of product, m.p. 153°-154.5°C.

EXAMPLES II to XV

The compounds shown in Table I were prepared by the method of Example I, using the appropriate cyclic amine and 4-sulphamoyl-benzene sulphonyl chloride as starting materials.

The compounds of Table I are represented by the formula: ##SPC9##

                                      TABLE I                                      __________________________________________________________________________                                    Analysis                                        Example                                                                             N-hetereocycle     m.p. °C.                                                                       Theoretical in brackets                         __________________________________________________________________________                                    %C    %H  %N                                    II                      218-20 46.36 5.73                                                                               8.35                                                                 (46.66                                                                               5.59                                                                               7.78)                                 III                     144-5  43.20 5.60                                                                               8.47                                                                 (43.11                                                                               5.43                                                                               8.38)                                 IV                      176-79 44.82 5.79                                                                               8.04                                                                 (44.83                                                                               5.80                                                                               7.79)                                 V                       177-78 49.13 6.74                                                                               7.31                                                                 (49.22                                                                               6.71                                                                               7.18)                                 VI                      217    42.97 4.91                                                                               7.72                                                                 (43.11                                                                               4.97                                                                               7.73)                                 VII                     173-74 45.07 5.64                                                                               8.73                                                                 (45.28                                                                               5.70                                                                               8.80)                                 VIII                    214-216                                                                               46.84 6.01                                                                               8.27                                                                 (47.00                                                                               6.07                                                                               8.43)                                 IX                      193    43.16 5.47                                                                               8.09                                                                 (43.11                                                                               5.43                                                                               8.38)                                 X                       172-174                                                                               40.87 5.10                                                                               8.95                                                                 (41.24                                                                               5.04                                                                               8.75)                                 XI                      220-221                                                                               43.43 5.26                                                                               9.16                                                                 (43.40                                                                               5.30                                                                               9.21)                                 XII                     179-180                                                                               41.41 5.15                                                                               8.16                                                                 (41.14                                                                               5.18                                                                               8.00)                                 XIII                    192-193                                                                               39.47 4.67                                                                               9.09                                                                 (39.22                                                                               4.61                                                                               9.15)                                 XIV                     194-195.5                                                                             37.81 4.38                                                                               8.45                                                                 (37.27                                                                               4.38                                                                               8.69)                                 XV                      228-230                                                                               41.00 4.95                                                                               8.73                                                                 (41.25                                                                               5.04                                                                               8.75)                                 __________________________________________________________________________

EXAMPLE XVI 4-(4-Oxopiperidinosulphonyl)-benzene sulphonamide

A solution of the product of Example VII (1.2 g.) in 30% aquenous dimethylformamide (50 ml.) and concentrated hydrochloric acid (1.5 m.) is stirred under reflux for 1 hour. The mixture is evaporated to small volume and the resulting precipitate is filtered off and recrystallized from an acetone-hexane mixture to give the desired product (.95 g.), m.p. 194°-195°C.

Analysis: Found C, 42.64; H, 4.67; N, 8.54%.

Calculated for C₁₁ H₁₄ N₂ O₅ S₂ : C, 41.50; H, 4.40; N, 8.80%.

The activity of compounds of the invention as cerebral vasodilators is determined by the following method. Cats are anaesthetised with chloralose (80mg/kg, intravenously) after induction with halothane, nitrous oxide-oxygen (3:1 v/v). The animals are allowed to breathe normal room air and the rate and depth of respiration, heart rate and femoral arterial pressure are recorded. Electromagnetic flow probes are placed around the ipsilateral vertebral artery. Zero flow is established by momentarily occluding the arteries in order to calibrate the flow probes. The test compound (dissolved in N/10 sodium hydroxide in isotonic saline with warming and mixing and then back titration to pH 1 with dilute hydrochloric acid) is given at 10 or 25 mg/kg via a femoral vein and readings are taken at intervals for up to 2 hours. Control observations after administration of the saline vehicle alone are also made. The criterion for selecting the preferred compounds is on the basis of increases in ipsilateral vertebral arterial flow at 10 mg/kg which are sustained over a period of 30 minutes as shown in Table II. Blood flow is assessed by measuring the peak (systolic) pulsative flow and the mean pulsatile flow.

The products of Examples I, IX and XV have been found to give significant increases in peak and mean pulsatile flow at 10 mg/kg. Table II hereinafter summarizes results obtained with representative cerebral vasodilators of the present invention in accordance with this method.

                  TABLE II                                                         ______________________________________                                                    Activity Data.sup.(1)                                               Compound of  Dose                                                              Example      (mg/kg)     IVF:%       t                                         ______________________________________                                         I            10          40          30-60                                                  25          36          30-60                                     III          25          11          5-15                                      IX           10          20          5-10                                                   25          60          >40                                       X            10          16          5-6                                                    25          14          10                                        XIII         10          6           10                                                     25          19          40-50                                     XV           10          20          5-10                                                   25          80          70-80                                     ______________________________________                                          .sup.(1) mean maximum increase in blood flow (%) and duration of action i      minutes (t). IVF ipsilateral vertebral arterial flow.                    

    EXAMPLE XVII                                                                   Tablet formulation                                                                                   mg/tablet                                                ______________________________________                                         Active ingredient.sup.(1)                                                                              100.0                                                  glycine                 320.7                                                  PEG 6000.sup.(2)        40.0                                                   Myrj 52                 20.0                                                   magnesium stearate      4.9                                                    gelatin                 2.4                                                                            488.0                                                  ______________________________________                                          .sup.(1) mean particle diameter (from surface area/g) less than 16             microns.                                                                       .sup.(2) polyoxyethylene glycol of mean molecular weight 6000.                 .sup.(3) a foodstuffs quality surfactant: polyoxyethylene stearate.      

The active compound and glycine are granulated with an aqueous solution of the PEG 6000, Myrj 52 and gelatin, prior to adding the magnesium stearate and tableting in the usual way.

    ______________________________________                                         EXAMPLE XVIII                                                                  Capsule formulation                                                                                  mg/capsule                                               ______________________________________                                         Active ingredient.sup.(1)                                                                              100.0                                                  PEG 6000.sup.(2)        280.0                                                  Myrj 52                 20.0                                                                           400.0                                                  ______________________________________                                          .sup.(1) mean particle diameter less than 3 microns.                           .sup.(2) and .sup.(3) as in Example XVII.                                

The active compound is ball-milled in water to achieve the small particle size, mixed with the PEG 6000 and Myrj 52 as a paste and then dried at 40°C. to form a powder which is then filled into capsules in the usual way.

    ______________________________________                                         EXAMPLE XIX                                                                    Parenteral formulation                                                                       mg/ml                                                            ______________________________________                                         Active ingredient                                                                              7.5                                                            sodium chloride 7.9                                                            sodium hydroxide                                                                               (sufficient in pH adjustment)                                  water           (sufficient to make up volume)                                 ______________________________________                                    

The active ingredient and sodium chloride are dissolved in sterile, pyrogen-free and carbon dioxide-free water under hydroxide and the volume made up with similar water. The solution is then filled into 5 or 10 ml. ampoules through a filter and autoclaved at 115°C. for 30 minutes. 

What is claimed is:
 1. A process for increasing cerebral blood blow in a subject which comprises admistering to said subject a cerebral blood flow increasing amount of a compound selected from the group consisting of ##SPC10##and their salts with pharmaceutically acceptable cations wherein n and m are each two or three; X is oxygen or sulfur; R² and R³, when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms and R² and R³, when taken together, are alkylene having 2 to 4 carbon atoms.
 2. The process of claim 1 wherein X is oxygen.
 3. The process of claim 2 wherein each of R² and R³ is alkyl having 1 to 4 carbon atoms.
 4. The process of claim 1 wherein m and n are each 2, X is oxygen, R² is 3-methyl and R³ is 5-methyl. 